Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice

Salvatore Cuzzocrea; Emanuela Mazzon; Tiziana Genovese; Concetta Crisafulli; Woo Kee Min; Rosanna Di Paola; Carmelo Muià; Jia He Li; Giuseppe Malleo; Weizhen Xu; Edmond Massuda; Emanuela Esposito; Jie Zhang; Zhao Qi Wang

doi:10.1016/j.freeradbiomed.2006.09.025

Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice

Salvatore Cuzzocrea, Emanuela Mazzon, Tiziana Genovese, Concetta Crisafulli, Woo Kee Min, Rosanna Di Paola, Carmelo Muià, Jia He Li, Giuseppe Malleo, Weizhen Xu, Edmond Massuda, Emanuela Esposito, Jie Zhang, Zhao Qi Wang

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG₁₁₀KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-α and IL-1β and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.

Original language	English (US)
Pages (from-to)	90-105
Number of pages	16
Journal	Free Radical Biology and Medicine
Volume	42
Issue number	1
DOIs	https://doi.org/10.1016/j.freeradbiomed.2006.09.025
State	Published - Jan 1 2007
Externally published	Yes

Keywords

Apoptosis
Colitis
IL-1β
Inflammation
PARG inhibitor
PARG110 deletion
TNF-α

ASJC Scopus subject areas

General Medicine
Toxicology
Clinical Biochemistry

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10.1016/j.freeradbiomed.2006.09.025

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Cuzzocrea, S., Mazzon, E., Genovese, T., Crisafulli, C., Min, W. K., Di Paola, R., Muià, C., Li, J. H., Malleo, G., Xu, W., Massuda, E., Esposito, E., Zhang, J., & Wang, Z. Q. (2007). Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice. Free Radical Biology and Medicine, 42(1), 90-105. https://doi.org/10.1016/j.freeradbiomed.2006.09.025

Cuzzocrea, S, Mazzon, E, Genovese, T, Crisafulli, C, Min, WK, Di Paola, R, Muià, C, Li, JH, Malleo, G, Xu, W, Massuda, E, Esposito, E, Zhang, J & Wang, ZQ 2007, 'Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice', Free Radical Biology and Medicine, vol. 42, no. 1, pp. 90-105. https://doi.org/10.1016/j.freeradbiomed.2006.09.025

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title = "Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice",

abstract = "Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG110KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-α and IL-1β and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.",

keywords = "Apoptosis, Colitis, IL-1β, Inflammation, PARG inhibitor, PARG110 deletion, TNF-α",

author = "Salvatore Cuzzocrea and Emanuela Mazzon and Tiziana Genovese and Concetta Crisafulli and Min, {Woo Kee} and {Di Paola}, Rosanna and Carmelo Mui{\`a} and Li, {Jia He} and Giuseppe Malleo and Weizhen Xu and Edmond Massuda and Emanuela Esposito and Jie Zhang and Wang, {Zhao Qi}",

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AU - Cuzzocrea, Salvatore

AU - Mazzon, Emanuela

AU - Genovese, Tiziana

AU - Crisafulli, Concetta

AU - Min, Woo Kee

AU - Di Paola, Rosanna

AU - Muià, Carmelo

AU - Li, Jia He

AU - Malleo, Giuseppe

AU - Xu, Weizhen

AU - Massuda, Edmond

AU - Esposito, Emanuela

AU - Zhang, Jie

AU - Wang, Zhao Qi

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG110KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-α and IL-1β and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.

AB - Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG110KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-α and IL-1β and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.

KW - Apoptosis

KW - Colitis

KW - IL-1β

KW - Inflammation

KW - PARG inhibitor

KW - PARG110 deletion

KW - TNF-α

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Role of poly(ADP-ribose) glycohydrolase in the development of inflammatory bowel disease in mice

Abstract

Keywords

ASJC Scopus subject areas

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